Changes in tubular dysfunction marker levels in parallel with the levels of copper, rather than cadmium, in urine of middle-aged women in non-polluted areas

Objective This study was initiated to investigate if and to what extent the elevations in urinary alpha(1)- and beta(2)-microglobulins (alpha(1)-MG and beta(2)-MG, respectively) are specific to Cd nephro-toxicity. Methods Stored urine samples, collected from 1,000 adult women in 11 prefectures all over Japan, were analysed for eight elements (Ca, Cd, Co, Cu, Mg, Mn, Ni and Zn), alpha(1)-MG, beta(2)-MG, creatinine (CR) and specific gravity (SG); the data were cited from previous publications. The levels of eight elements and two MGs were expressed as observed and after correction for CR or SG (1.016). Age, CR and SG distributed normally, whereas two MGs and eight elements distributed log-normally. The 1,000 cases were classified into quartiles (i.e., 250 cases/group) of the lowest to the highest values (Groups A to D) for each element. Results alpha(1)-MG and beta(2)-MG increased as a function of Ca, Cd and Cu when corrected for CR, and the two MGs increased in parallel only with Cd and Cu after SG correction. Prevalence of alpha(1)-MG-uria (cut-off values; 5.3 and 6.5 mg/g cr or l) and beta(2)-MG-uria (cut-off values; 300 and 400 mu g/g cr or l) was elevated with increasing Ca, Cd and Cu when corrected for CR, but only with Cd and Cu when corrected for SG. Multiple regression analysis of 353 cases of 50-59 year-old women with the eight element levels as independent variables and one of the two MGs as a dependent variable showed that Cu was the most influential element, and both Cd and Zn were less influential. Conclusions Urinary levels of alpha(1)-MG and beta(2)-MG among women with no environmental Cd exposure correlated more closely with Cu levels than Cd levels in urine. The observation suggests that sub-clinical elevation in alpha(1)-MG and beta(2)-MG is not always attributable to nephro-toxicity of Cd, and that consideration on possible effects of other elements such as Cu is necessary.